Surgical Adjuvant Composition and Associated Methods of Use

ABSTRACT

Disclosed herein are surgical adjuvant compositions for ameliorating tissue and cellular necrosis and/or apoptosis. In addition, surgical methods are described which include the use of the adjuvant of the composition to reduce tissue and cellular necrosis and/or apoptosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 12/791,046 filed Jun. 1, 2010, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a surgical adjuvant composition thatprovides for reduced tissue and cellular necrosis and/or apoptosis. Thecomposition is particularly useful, for example, for use in arthroscopicsurgical procedures and other minimally invasive endoscopic procedureswhere an irrigant is useful.

BACKGROUND

Arthroscopic joint surgery is one of the most commonly performedprocedures in surgical practice and its use is steadily increasing. Forexample, more than 2 million arthroscopic procedures were performed inthe United States in 2003, and that number is steadily increasing. InCanada, thousands of arthroscopic procedures are performed every yearwith some procedures being performed completely arthroscopically asopposed to traditional open approaches.

One major advantage of arthroscopic surgery is its minimal invasivefashion which limits surgical wounds, bleeding, and in particular,limits post-operative pain and recovery time. During arthroscopy,irrigating solutions are used to distend and flush the joint. Two of themost commonly used irrigating solutions are saline and Ringer's lactate.Despite the relative safety of their use intra-vascularly, the short andlong term effects and relative safety of their use in other environmentsis unclear. Furthermore the prolonged bathing of articular tissue inthese foreign environments is unclear. In fact, there is mountingevidence that commonly used fluids and drugs given intra-articularly maybe detrimental to joint tissue viability.

For example, in an effort to improve post-operative pain control andlimit systemic side effects, the use of intra-articular localanesthetics (e.g. bupivacaine, xylocaine, ropivicaine) has gainedpopularity. Local anesthetic use following arthroscopic surgery isroutinely performed as a single dose intra-articular injection.Furthermore, to provide even longer term relief, continuous infusion ofintra-articular local anesthetics is commonly performed for up to 48-72hours.

However, a number of recent in vitro studies have demonstrated thatlocal anesthetics are, in fact, highly toxic to articular tissues. Forexample, several studies have documented that exposure to localanesthetics decreased cellular viability of articular tissues in a doseand duration dependent manner. Additionally, many have reported acutechondrolysis (i.e. cartilage cell death and loss of tissue integrity)following prolonged intra-articular local anesthetic infiltration.

During the course of arthroscopic surgery, it is common to useelectrical cauterization and, or mechanical drilling, burring, orgrinding to effect changes to the tissue. These procedures generateexcessive heat that can lead to collateral morbidity to the cells andtissues near the site of repair. In addition, the instruments usedduring an arthroscopic procedure can impact and cut the articularcartilage, insults that have been linked to chondrocyte death (Am JSports Med 2009, 37: 2318-23).

Our studies have investigated the effects of irrigant fluids (e.gsaline, ringers lactate) on tissue viability (FIG. 1, See Appendix).Theeffects of irrigant fluids on tissue viability has also beeninvestigated. Studies using both in vitro and in vivo animal models,have demonstrated detrimental effects of non-physiologic fluids (e.g.normal saline, ringers lactate) on cartilage morphology, ultrastructure,metabolism, and biomechanics (J Bone Joint Surg Am 1983, June65(5):629-3). Based on this data there is an ongoing need to develop aphysiologic solution applicable to medical and veterinary surgical needsthat can ameliorate the problem of tissue destruction resulting from thedetrimental effects of non-physiologic surgical adjuvants and irrigants,as well as the collateral mechanical and thermal damage associated withsurgical intervention.

SUMMARY

Presently described are surgical adjuvant/irrigant compositions thatsurprisingly and unexpectedly ameliorate or reduce tissue and cellularnecrosis and/or apoptosis, and associated methods of use andmanufacture. The compositions described herein can replace the irrigantsnormally or currently used in arthroscopy.

In one aspect, compositions are provided that are useful as surgicaladjuvants or irrigants, for example, replacing the irrigant normallyused in arthroscopy. For example, in certain embodiments the compositioncomprises a combination of isotonic phosphate buffered saline, highmolecular weight dextran, ascorbate, transferrin, and the poloxamersurfactant P188. In another aspect, the surgical adjuvant composition ofthe invention further comprises an anesthetic, for example, a localanesthetic and/or epinephrine injected into the joint space during orfollowing the procedure.

In another aspect, the invention provides compositions for use as acarrier or an additive to a surgical irrigant.

In another aspect, the invention provides methods of performing asurgical procedure using the composition of the invention. In certainembodiments, this aspect includes methods for performing arthroscopicsurgical procedures using the composition of the invention. In anotheraspect, the invention provides carriers for drug delivery to the jointspace, or the site of surgical intervention.

In another aspect, the invention provides compositions useful as abiological fluid replacement.

The preceding general areas of utility are given by way of example onlyand are not intended to be construed as limiting on the scope of theinvention. Additional objects and advantages of the present inventionwill be appreciated by one of ordinary skill in the art in light of theinstant claims, description, and examples. For example, the variousaspects and embodiments of the invention may be utilized in numerouscombinations, all of which are expressly contemplated by the presentdescription. These additional advantages objects and embodiments areexpressly included within the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating an embodiment of the invention and are not to be construedas limiting the invention. Further objects, features and advantages ofthe invention will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the invention, in which:

FIG. 1 shows the effects of the composition of the invention on cellviability compared to bathing solutions of saline, Ringer's Lactate, andphosphate buffered saline. Cell counts were taken at about 24 and about48 hours in the absence and presence of anesthetic. T=0: initialviability; PBS: phosphate buffered saline; Ringers: Ringer's Lactate;bup: bupivacaine; epi: epinephrine; AG (“arthroguard”) exemplarycomposition provided by the invention (“arthroguard”). Error bars showstandard deviation.

FIG. 2 demonstrates the effects of an exemplary composition provided bythe invention (i.e., arthroguard) on chondrocyte death in thesuperficial zone after exposure to saline, and ringers. Full thicknessdiscs (6 mm diameter) of articular cartilage from the bovineradial-carpal joint are immersed in various solutions for 24 and 48hours, after which the cartilage is cut into 70 μm sections (sectionscut perpendicular to the articular surface) on a vibratome and stainedwith Syto 13 (Molecular Probes) and ethidium bromide to assesschondrocyte viability. The superficial zone is taken as the region fromthe articular surface to 1/10 the distance to the calcified zone.

FIG. 3: Immunofluorescence microscopy showing the effects on cellviability of solutions containing bupivacaine (bupivacaine is suppliedas a 2.5 mg/mL [0.25%] solution from the manufacturer). Full thicknessdiscs of articular cartilage from the bovine radial-carpal joint wereimmersed in 1.25 mg/mL (0.125%) solutions of bupivacaine (diluted from2.5/mg/mL to 1.25 mg/mL (0.25% to 0.125%) using phosphate bufferedsaline) for 24 hours, after which the cartilage is cut into 70 μmsections on a vibratome and stained with Syto 13 (Molecular Probes) andethidium bromide to assess chondrocyte viability. Green fluorescenceindicates live articular chondrocytes, red fluorescence indicates deadarticular chondrocytes.

FIG. 4 demonstrates the effects on cell viability of solutionscontaining epinephrine and bupivacaine. Full thickness discs (6 mmdiameter) of articular cartilage from the bovine radial-carpal jointwere immersed in solutions of bupivacaine, bupivacaine with epinephrine(manufacturers solution), bupivacaine with exogenously added epinephrine(5 ug/mL final concentration). Bupivacaine concentrations (with orwithout epinephrine) for each solution were either 2.5/mg/mL [0.25%] or1.25 mg/mL (0.25% to 0.125%) (diluted using phosphate buffered saline)for 24 hours, after which the cartilage is cut into 70 μm sections on avibratome and stained with Syto 13 (Molecular Probes) and ethidiumbromide to assess chondrocyte viability.

FIG. 5: Immunofluorescence microscopy showing the effects on cellviability of solutions containing bupivacaine (1.25 mg/mL [0.125%]) andarthroguard. In these experiments, 2.5 mg/mL [0.25%] bupivacaine wascombined with arthroguard to yield a final concentration of 1.25 mg/mL[0.125%] bupivacaine in arthroguard. Green fluorescence indicates livearticular chondrocytes, red fluorescence indicates dead articularchondrocytes.

FIG. 6: Canine synovioctyes in suspension are immersed in eitherphosphate buffered saline (PBS) or arthroguard and are held at 45° C.for up to 2.5 hours. Cell viability is assessed using paravital dyesunder ultraviolet illumination to indicate plasma membrane integrity.The figure shows the average percentage of viable cells in four separatefields (10× objective). The bars show the standard deviation of themean.

FIG. 7: Bovine chondrocytes suspended for 12 hrs. at 37° C. in varioussolutions of phosphate buffered saline (PBS), bupivacaine (1.25 mg/mL[0.125%]), arthroguard and saline. In these experiments, 2.5 mg/mL[0.25%] bupivacaine was combined with arthroguard to yield a finalconcentration of 1.25 mg/mL [0.125%] bupivacaine in arthroguard. for 12hrs. Cell viability is assessed by membrane integrity dyes.

As indicated above, the figures are provided for exemplary purposes onlyand are not to be construed as limiting. For example, as would beunderstood by those skilled in the art, any of the features described inthe figures can be combined with any other embodiment or embodiments inany conceivable combination, all of which are contemplated by theinventors, and encompassed by the present claims.

DETAILED DESCRIPTION

The present invention relates to a surgical adjuvant/irrigantcomposition that surprisingly and unexpectedly ameliorates or reducestissue and cellular necrosis and/or apoptosis.

The following is a detailed description of the invention provided to aidthose skilled in the art in practicing the present invention. Those ofordinary skill in the art may make modifications and variations in theembodiments described herein without departing from the spirit or scopeof the present invention. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. The terminology used in the description of the invention hereinis for describing particular embodiments only and is not intended to belimiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges which may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

Although any methods and materials similar or equivalent to thosedescribed herein can also be used in the practice or testing of thepresent invention, the preferred methods and materials are nowdescribed. All publications mentioned herein are expressly incorporatedherein by reference in their entirety to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references, the entiredisclosures of which are incorporated herein by reference, provide oneof skill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2^(nd) ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5^(th) Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, theHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms may have meanings ascribed to them below, unlessspecified otherwise. However, it should be understood that othermeanings that are known or understood by those having ordinary skill inthe art are also possible, and within the scope of the presentinvention. All publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting.

As described above, the use of saline as an irrigant may lead tochondrocyte necrosis and/or apoptosis in the superficial zone ofarticular cartilage. The present invention relates to the surprisingdiscovery that irrigation of a surgical site using a solution comprisingisotonic phosphate buffered saline in combination with at least one of ahigh molecular weight dextran, ascorbate, transferrin or poloxamersurfactant P188 reduces the necrosis and/or apoptosis in the superficialzone and elsewhere in the articular cartilage. Accordingly, the presentinvention provides a composition comprising isotonic phosphate bufferedsaline in combination with at least one of a high molecular weightdextran, ascorbate, transferrin or poloxamer surfactant P188. In anotherembodiment, the composition provided by the invention comprises isotonicphosphate buffered saline, and polyoxamer surfactant P188 in combinationwith at least one of a high molecular weight dextran, ascorbate, ortransferrin. In another embodiment, the composition provided by theinvention provides, comprises isotonic phosphate buffered saline,polyoxamer surfactant P188, a high molecular weight dextran, ascorbate,and transferrin. The compositions provided by the invention appear tofunction synergistically to promote the viability of cells when exposedto cytotoxic agents, including, for example, local anesthetics.

In addition, the use of local anaesthetics and/or epinephrine in thejoint space has been shown to lead to chondrocyte necrosis and/orapoptosis. However, it has been surprisingly and unexpectedly discoveredthat irrigation of a surgical site using a solution comprising isotonicphosphate buffered saline, and at least one of poloxamer surfactantP188, high molecular weight dextran, ascorbate, transferring or acombination thereof, reduces the necrosis and/or apoptosis caused bylocal anesthetics and/or epinephrine. In certain embodiments, thesolution comprises isotonic phosphate buffered saline, poloxamersurfactant P188, and at least one or more of a high molecular weightdextran, ascorbate, transferrin or a combination thereof.

In another aspect, the invention provides compositions for the deliveryof an anesthetic, local or general. For example, the compositioncomprises isotonic phosphate buffered saline in combination with atleast one of a high molecular weight dextran, ascorbate, transferrin orpoloxamer surfactant P188 in combination with an anesthetic. Manyanesthetics are known by those of skill in the art and can be used withthe present invention. For example, in any of the embodiments describedherein, the composition may contain morphine, fentanyl, gabapentin,Opioids, Alfentanil, Anileridine, Fentanyl, Phenoperidine. Remifentanil,Sufentanil, Neuroactive steroids Alfaxalone, Minaxolone, Droperidol,Etomidate, Fospropofol, gamma-Hydroxybutyric acid, Ketamine/Esketamine,Midazolam, Propanidid, or Propofol.anesthetic. In certain additionalembodiments, the composition comprises a local anesthetic. Examples oflocal anesthetics that can be used with any of the embodiments describedherein, include bupivacaine, xylocaine/lidocaine, ropivacaine, andcombinations thereof. Accordingly, in another embodiment, thecomposition comprises isotonic phosphate buffered saline in combinationwith at least one of a high molecular weight dextran, ascorbate,transferrin or poloxamer surfactant P188 in combination with at leastone of bupivacaine, xylocaine/lidocaine, ropivacaine, or a combinationthereof.

In any of the embodiments described herein, the composition may furthercomprise an effective amount of epinephrine or other monoamine.Epinephrine, also known as adrenaline, is a hormone andneurotransmitter. When produced in the body it increases heart rate,contracts blood vessels and dilates air passages and participates in thefight-or-flight response of the sympathetic nervous system. It is acatecholamine, a monoamine produced only by the adrenal glands from theamino acids phenylalanine and tyrosine. Due to its vasoconstrictiveeffects, adrenaline is the drug of choice for treating anaphylaxis.

Although the precise mode of action of the irrigant remains to be fullyunderstood, and without being limited to any particular theory, theindividual components of the arthroguard solution are hypothesized toact both individually and collectively to prevent cell death due toexposure to anaesthetics and/or epinephrine. For example, phosphatebuffered saline may provide a pH buffer as well as essential ions forosmotic balance. Dextran may provide a non-ionic osmoticum that mayreduce or prevent swelling of the cells and/or tissue. Ascorbate is anantioxidant that may reduce or prevent lipid peroxidation, which can bea precursor to apoptosis. Transferrin binds any free ferrous ions whichmay otherwise react through the Fenton reaction to produce hydroxylradicals that react non-specifically with lipids and other organicmolecules, possibly initiating apoptosis. The poloxamer P188 maystabilize membrane pores and/or blebs that form in the initial stages ofapoptosis and many types of necrosis.

In any of the embodiments encompassed herein, the concentrations ofreagents may be within the following ranges: (i) dextran: from about 0.1mg/mL to about 1000 mg/mL, (ii) P188: from about 0.1 mg/mL to about 100mg/mL, (iii) ascorbate: from about 0.1 mM to about 100 mM, (iv)transferrin: from about 10⁻⁷ M to about 10⁻⁴M.

Membrane stabilization may be an important intervention that haltsand/or reverses the apoptotic progression allowing cells to recover fromthe injury that precipitated the cascade. Membrane stabilization mayalso allow the resealing of membrane pores that accompany many types ofnecrosis, preventing cell lysis that may be the endpoint of the necroticprocess. Both apoptotic and necrotic cell death progressions may beinitiated by singular events or multiple sub-lethal injuries, thereforethese agents may act individually to prevent cell death in somecircumstances but collectively in others. The synergistic effects of thereagents may not manifest themselves in all situations nevertheless theymay still retain crucial importance for the effectiveness of thecompositions provided by the invention.

In additional embodiments, compositions provided by the invention maycomprise any pharmaceutically acceptable carriers or excipients,including sugars, sugar alcohols, such as lactose, sucrose, trehalose,mannitol and sorbitol; cellulose preparations such as maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose; water, glycols, oils, alcohols, coloring agents,flavoring agents, preservatives, and/or polyvinylpyrrolidone (PVP);granulating agents; binding agents; cross-linked polyvinylpyrrolidone;agar; or alginic acid or a salt thereof such as sodium alginate.

In any of the embodiments described herein, the composition provided bythe invention may be combined with one or more cell and/or tissuebiocompatible solutions or cell/tissue media. For example, knownbiocompatible solutions or cell media include Ringer's solution,Ringer's Lactate, saline, balanced salt solutions, phosphate bufferedsaline, biopreservation solutions, Eurocollins solution, UW solution,Hank's buffered salt solution, Earl's balanced salt solution, Dulbecco'sphosphate buffered saline or combinations thereof. Additionalbiocompatible solutions or cell/tissue media are known and may becomeknown to those of skill in the art and their use in combination with thecompositions of the invention are explicitly contemplated as beingwithin the scope of the invention.

In another aspect, the invention provides a composition useful as asurgical adjuvant for the amelioration of tissue and/or cellular damage,for example, due to a surgical procedure. Accordingly, the presentinvention provides a surgical adjuvant composition comprising isotonicphosphate buffered saline in combination with at least one of a highmolecular weight dextran, ascorbate, transferrin or poloxamer surfactantP188. In another embodiment, the invention provides a surgical adjuvantcomposition comprising isotonic phosphate buffered saline, andpolyoxamer surfactant P188 in combination with at least one of a highmolecular weight dextran, ascorbate, or transferrin. In anotherembodiment, the invention provides a surgical adjuvant compositioncomprising isotonic phosphate buffered saline, polyoxamer surfactantP188, a high molecular weight dextran, ascorbate, and transferrin.

The surgical adjuvant as described herein ameliorates and/or preventstissue and/or cellular damage due to a surgical procedure, for example,an invasive or minimally invasive procedure (e.g., endoscopic,thoracoscopic or laparoscopic procedure). Therefore, in another aspect,the invention provides a method for ameliorating and/or preventingtissue and/or cellular damage due to an invasive or minimally invasivesurgical procedure, wherein the composition ameliorates tissue orcellular damage. In an embodiment of this aspect, the method comprisesthe steps of administering to the patient an effective amount of theadjuvant as described herein at any point during the procedure. Forexample, the surgical adjuvant composition can be administered before,during, and/or after the surgical procedure. In still anotherembodiment, the surgical adjuvant composition is administered (i.e.,perfused) continuously through or over the surgical site from prior tothe procedure and continuing until some time after the conclusion of theprocedure. Of course, the appropriate amount of adjuvant and/or rate ofperfusion to be used in any instance can be readily determined by theskilled artisan in view of the present teachings and knowledge of thoseskilled in the art.

In another aspect, the composition provided by the invention may be usedas a carrier and/or diluent for the delivery of one or morepharmaceutical or biologically beneficial and/or biologically activetherapeutic agents. For example, in an exemplary embodiment, the carriercomprises an isotonic phosphate buffered saline, and at least one ofpoloxamer surfactant P188, high molecular weight dextran, ascorbate,transferrin or a combination thereof, in combination with at least oneof, for example, a vitamin, coenzyme, herbal extract or other dietarysupplement ingredient, saccharide, carbohydrate, glycan, proteoglycan,small molecule drug, antibody and/or antibody fragment, protein,peptide, or the like. In still another embodiment, the carrier comprisesan isotonic phosphate buffered saline, a poloxamer surfactant P188, andat least one of a high molecular weight dextran, ascorbate, transferrinor a combination thereof, in combination with at least one of, forexample, a vitamin, coenzyme, herbal extract or other dietary supplementingredient, saccharide, carbohydrate, glycan, proteoglycan, smallmolecule drug, antibody and/or antibody fragment, protein, peptide, orthe like.

Specific examples of biologically beneficial ingredients that can beutilized in any of the embodiments described herein include: hyaluronicacid, growth factors (e.g. VEGF, TGF family), therapeutic antibodies(e.g., Humira), substance P, glucosamine, chondroitin sulphate,glycosaminoglycans, pain control agents (e.g morphine), synovial fluidand/or its components, steroids and derivatives. It should further beunderstood that the combinations which are to be included within thisinvention are those combinations useful for their intended purpose. Theagents set forth below are illustrative for purposes and not intended tobe limited. The combinations which are part of this invention can be thecompositions provided by the present invention and at least oneadditional agent selected from the lists below. The combination can alsoinclude more than one additional agent, e.g., two or three additionalagents if the combination is such that the formed composition canperform its intended function.

Thus, in additional embodiments, the compositions provided by theinvention can optionally further comprise an effective amount of atleast one compound or protein selected from at least one of ananti-infective drug, a cardiovascular (CV) system drug, a centralnervous system (CNS) drug, an autonomic nervous system (ANS) drug, arespiratory tract drug, a gastrointestinal (GI) tract drug, a hormonaldrug, a drug for fluid or electrolyte balance, a hematologic drug, anantineoplastic, an immunomodulation drug, an ophthalmic, otic or nasaldrug, a topical drug, a nutritional drug or the like. Such drugs arewell known in the art, including formulations, indications, dosing andadministration for each presented herein (see, e.g., Nursing 2001Handbook of Drugs, 21.sup.st edition, Springhouse Corp., Springhouse,Pa., 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson,Stang, Prentice-Hall, Inc, Upper Saddle River, N.J.; PharmcotherapyHandbook, Wells et al., ed., Appleton & Lange, Stamford, Conn., eachentirely incorporated herein by reference).

The anti-infective drug can be at least one selected from amebicides orat least one antiprotozoals, anthelmintics, antifungals, antimalarials,antituberculotics or at least one antileprotics, aminoglycosides,penicillins, cephalosporins, tetracyclines, sulfonamides,fluoroquinolones, antivirals, macrolide anti-infectives, andmiscellaneous anti-infectives. The CV drug can be at least one selectedfrom inotropics, antiarrhythmics, antianginals, antihypertensives,antilipemics, and miscellaneous cardiovascular drugs. The CNS drug canbe at least one selected from normarcotic analgesics or at least oneselected from antipyretics, nonsteroidal anti-inflammatory drugs,narcotic or at least one opioid analgesics, sedative-hypnotics,anticonvulsants, antidepressants, antianxiety drugs, antipsychotics,central nervous system stimulants, antiparkinsonians, and miscellaneouscentral nervous system drugs. The ANS drug can be at least one selectedfrom cholinergics (parasympathomimetics), anticholinergics, adrenergics(sympathomimetics), adrenergic blockers (sympatholytics), skeletalmuscle relaxants, and neuromuscular blockers. The respiratory tract drugcan be at least one selected from antihistamines, bronchodilators,expectorants or at least one antitussive, and miscellaneous respiratorydrugs. The GI tract drug can be at least one selected from antacids orat least one adsorbent or at least one antiflatulent, digestive enzymeor at least one gallstone solubilizer, antidiarrheals, laxatives,antiemetics, and antiulcer drugs. The hormonal drug can be at least oneselected from corticosteroids, androgens or at least one anabolicsteroid, estrogen or at least one progestin, gonadotropin, antidiabeticdrug or at least one glucagon, thyroid hormone, thyroid hormoneantagonist, pituitary hormone, and parathyroid-like drug. The drug forfluid and electrolyte balance can be at least one selected fromdiuretics, electrolytes or at least one replacement solution, acidifieror at least one alkalinizer. The hematologic drug can be at least oneselected from hematinics, anticoagulants, blood derivatives, andthrombolytic enzymes. The antineoplastics can be at least one selectedfrom alkylating drugs, antimetabolites, antibiotic antineoplastics,antineoplastics that alter hormone balance, and miscellaneousantineoplastics. The immunomodulation drug can be at least one selectedfrom immunosuppressants, vaccines or at least one toxoid, antitoxin orat least one antivenin, immune serum, and biological response modifier.The ophthalmic, otic, and nasal drugs can be at least one selected fromophthalmic anti-infectives, ophthalmic anti-inflammatories, miotics,mydriatics, ophthalmic vasoconstrictors, miscellaneous ophthalmics,otics, and nasal drugs. The topical drug can be at least one selectedfrom local anti-infectives, scabicides or at least one pediculicide ortopical corticosteroid. The nutritional drug can be at least oneselected from vitamins, minerals, or calorics. See, e.g., contents ofNursing 2001 Drug Handbook, supra.

The at least one amebicide or antiprotozoal can be at least one selectedfrom atovaquone, chloroquine hydrochloride, chloroquine phosphate,metronidazole, metronidazole hydrochloride, and pentamidine isethionate.The at least one anthelmintic can be at least one selected frommebendazole, pyrantel pamoate, and thiabendazole. The at least oneantifungal can be at least one selected from amphotericin B,amphotericin B cholesteryl sulfate complex, amphotericin B lipidcomplex, amphotericin B liposomal, fluconazole, flucytosine,griseofulvin microsize, griseofulvin ultramicrosize, itraconazole,ketoconazole, nystatin, and terbinafine hydrochloride. The at least oneantimalarial can be at least one selected from chloroquinehydrochloride, chloroquine phosphate, doxycycline, hydroxychloroquinesulfate, mefloquine hydrochloride, primaquine phosphate, pyrimethamine,and pyrimethamine with sulfadoxine. The at least one antituberculotic orantileprotic can be at least one selected from clofazimine, cycloserine,dapsone, ethambutol hydrochloride, isoniazid, pyrazinamide, rifabutin,rifampin, rifapentine, and streptomycin sulfate. The at least oneaminoglycoside can be at least one selected from amikacin sulfate,gentamicin sulfate, neomycin sulfate, streptomycin sulfate, andtobramycin sulfate. The at least one penicillin can be at least oneselected from amoxcillin/clavulanate potassium, amoxicillin trihydrate,ampicillin, ampicillin sodium, ampicillin trihydrate, ampicillinsodium/sulbactam sodium, cloxacillin sodium, dicloxacillin sodium,mezlocillin sodium, nafcillin sodium, oxacillin sodium, penicillin Gbenzathine, penicillin G potassium, penicillin G procaine, penicillin Gsodium, penicillin V potassium, piperacillin sodium, piperacillinsodium/tazobactam sodium, ticarcillin disodium, and ticarcillindisodium/clavulanate potassium.

The at least one cephalosporin can be at least one selected fromcefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepimehydrochloride, cefixime, cefinetazole sodium, cefonicid sodium,cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitinsodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten,ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroximesodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine,and loracarbef. The at least one tetracycline can be at least oneselected from demeclocycline hydrochloride, doxycycline calcium,doxycycline hyclate, doxycycline hydrochloride, doxycycline monohydrate,minocycline hydrochloride, and tetracycline hydrochloride. The at leastone sulfonamide can be at least one selected from co-trimoxazole,sulfadiazine, sulfamethoxazole, sulfisoxazole, and sulfisoxazole acetyl.The at least one fluoroquinolone can be at least one selected fromalatrofloxacin mesylate, ciprofloxacin, enoxacin, levofloxacin,lomefloxacin hydrochloride, nalidixic acid, norfloxacin, ofloxacin,sparfloxacin, and trovafloxacin mesylate. The at least onefluoroquinolone can be at least one selected from alatrofloxacinmesylate, ciprofloxacin, enoxacin, levofloxacin, lomefloxacinhydrochloride, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, andtrovafloxacin mesylate. The at least one antiviral can be at least oneselected from abacavir sulfate, acyclovir sodium, amantadinehydrochloride, amprenavir, cidofovir, delavirdine mesylate, didanosine,efavirenz, famciclovir, fomivirsen sodium, foscarnet sodium,ganciclovir, indinavir sulfate, lamivudine, lamivudine/zidovudine,nelfinavir mesylate, nevirapine, oseltamivir phosphate, ribavirin,rimantadine hydrochloride, ritonavir, saquinavir, saquinavir mesylate,stavudine, valacyclovir hydrochloride, zalcitabine, zanamivir, andzidovudine. The at least one macroline anti-infective can be at leastone selected from azithromycin, clarithromycin, dirithromycin,erythromycin base, erythromycin estolate, erythromycin ethylsuccinate,erythromycin lactobionate, and erythromycin stearate. The at least onemiscellaneous anti-infective can be at least one selected fromaztreonam, bacitracin, chloramphenicol sodium sucinate, clindamycinhydrochloride, clindamycin palmitate hydrochloride, clindamycinphosphate, imipenem and cilastatin sodium, meropenem, nitrofurantoinmacrocrystals, nitrofurantoin microcrystals, quinupristin/dalfopristin,spectinomycin hydrochloride, trimethoprim, and vancomycin hydrochloride.(See, e.g., pp. 24-214 of Nursing 2001 Drug Handbook.)

The at least one inotropic can be at least one selected from aminonelactate, digoxin, and milrinone lactate. The at least one antiarrhythmiccan be at least one selected from adenosine, amiodarone hydrochloride,atropine sulfate, bretylium tosylate, diltiazem hydrochloride,disopyramide, disopyramide phosphate, esmolol hydrochloride, flecamideacetate, ibutilide fumarate, lidocaine hydrochloride, mexiletinehydrochloride, moricizine hydrochloride, phenyloin, phenyloin sodium,procainamide hydrochloride, propafenone hydrochloride, propranololhydrochloride, quinidine bisulfate, quinidine gluconate, quinidinepolygalacturonate, quinidine sulfate, sotalol, tocamide hydrochloride,and verapamil hydrochloride. The at least one antianginal can be atleast one selected from amlodipidine besylate, amyl nitrite, bepridilhydrochloride, diltiazem hydrochloride, isosorbide dinitrate, isosorbidemononitrate, nadolol, nicardipine hydrochloride, nifedipine,nitroglycerin, propranolol hydrochloride, verapamil, and verapamilhydrochloride. The at least one antihypertensive can be at least oneselected from acebutolol hydrochloride, amlodipine besylate, atenolol,benazepril hydrochloride, betaxolol hydrochloride, bisoprolol fumarate,candesartan cilexetil, captopril, carteolol hydrochloride, carvedilol,clonidine, clonidine hydrochloride, diazoxide, diltiazem hydrochloride,doxazosin mesylate, enalaprilat, enalapril maleate, eprosartan mesylate,felodipine, fenoldopam mesylate, fosinopril sodium, guanabenz acetate,guanadrel sulfate, guanfacine hydrochloride, hydralazine hydrochloride,irbesartan, isradipine, labetalol hydrochloride, lisinopril, losartanpotassium, methyldopa, methyldopate hydrochloride, metoprolol succinate,metoprolol tartrate, minoxidil, moexipril hydrochloride, nadolol,nicardipine hydrochloride, nifedipine, nisoldipine, nitroprussidesodium, penbutolol sulfate, perindopril erbumine, phentolamine mesylate,pindolol, prazosin hydrochloride, propranolol hydrochloride, quinaprilhydrochloride, ramipril, telmisartan, terazosin hydrochloride, timololmaleate, trandolapril, valsartan, and verapamil hydrochloride. The atleast one antilipemic can be at least one selected from atorvastatincalcium, cerivastatin sodium, cholestyramine, colestipol hydrochloride,fenofibrate (micronized), fluvastatin sodium, gemfibrozil, lovastatin,niacin, pravastatin sodium, and simvastatin. The at least onemiscellaneous CV drug can be at least one selected from abciximab,alprostadil, arbutamine hydrochloride, cilostazol, clopidogrelbisulfate, dipyridamole, eptifibatide, midodrine hydrochloride,pentoxifylline, ticlopidine hydrochloride, and tirofiban hydrochloride.(See, e.g., pp. 215-336 of Nursing 2001 Drug Handbook.)

The at least one normarcotic analgesic or antipyretic can be at leastone selected from acetaminophen, aspirin, choline magnesiumtrisalicylate, diflunisal, and magnesium salicylate. The at least onenonsteroidal anti-inflammatory drug can be at least one selected fromcelecoxib, diclofenac potassium, diclofenac sodium, etodolac, fenoprofencalcium, flurbiprofen, ibuprofen, indomethacin, indomethacin sodiumtrihydrate, ketoprofen, ketorolac tromethamine, nabumetone, naproxen,naproxen sodium, oxaprozin, piroxicam, rofecoxib, and sulindac. The atleast one narcotic or opioid analgesic can be at least one selected fromalfentanil hydrochloride, buprenorphine hydrochloride, butorphanoltartrate, codeine phosphate, codeine sulfate, fentanyl citrate, fentanyltransdermal system, fentanyl transmucosal, hydromorphone hydrochloride,meperidine hydrochloride, methadone hydrochloride, morphinehydrochloride, morphine sulfate, morphine tartrate, nalbuphinehydrochloride, oxycodone hydrochloride, oxycodone pectinate, oxymorphonehydrochloride, pentazocine hydrochloride, pentazocine hydrochloride andnaloxone hydrochloride, pentazocine lactate, propoxyphene hydrochloride,propoxyphene napsylate, remifentanil hydrochloride, sufentanil citrate,and tramadol hydrochloride. The at least one sedative-hypnotic can be atleast one selected from chloral hydrate, estazolam, flurazepamhydrochloride, pentobarbital, pentobarbital sodium, phenobarbitalsodium, secobarbital sodium, temazepam, triazolam, zaleplon, andzolpidem tartrate. The at least one anticonvulsant can be at least oneselected from acetazolamide sodium, carbamazepine, clonazepam,clorazepate dipotassium, diazepam, divalproex sodium, ethosuximde,fosphenyloin sodium, gabapentin, lamotrigine, magnesium sulfate,phenobarbital, phenobarbital sodium, phenyloin, phenyloin sodium,phenyloin sodium (extended), primidone, tiagabine hydrochloride,topiramate, valproate sodium, and valproic acid. The at least oneantidepressant can be at least one selected from amitriptylinehydrochloride, amitriptyline pamoate, amoxapine, bupropionhydrochloride, citalopram hydrobromide, clomipramine hydrochloride,desipramine hydrochloride, doxepin hydrochloride, fluoxetinehydrochloride, imipramine hydrochloride, imipramine pamoate,mirtazapine, nefazodone hydrochloride, nortriptyline hydrochloride,paroxetine hydrochloride, phenelzine sulfate, sertraline hydrochloride,tranylcypromine sulfate, trimipramine maleate, and venlafaxinehydrochloride. The at least one antianxiety drug can be at least oneselected from alprazolam, buspirone hydrochloride, chlordiazepoxide,chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam,doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride,hydroxyzine pamoate, lorazepam, mephrobamate, midazolam hydrochloride,and oxazepam. The at least one antipsychotic drug can be at least oneselected from chlorpromazine hydrochloride, clozapine, fluphenazinedecanoate, fluephenazine enanthate, fluphenazine hydrochloride,haloperidol, haloperidol decanoate, haloperidol lactate, loxapinehydrochloride, loxapine succinate, mesoridazine besylate, molindonehydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine,quetiapine fumarate, risperidone, thioridazine hydrochloride,thiothixene, thiothixene hydrochloride, and trifluoperazinehydrochloride. The at least one central nervous system stimulant can beat least one selected from amphetamine sulfate, caffeine,dextroamphetamine sulfate, doxapram hydrochloride, methamphetaminehydrochloride, methylphenidate hydrochloride, modafinil, pemoline, andphentermine hydrochloride. The at least one antiparkinsonian can be atleast one selected from amantadine hydrochloride, benztropine mesylate,biperiden hydrochloride, biperiden lactate, bromocriptine mesylate,carbidopa-levodopa, entacapone, levodopa, pergolide mesylate,pramipexole dihydrochloride, ropinirole hydrochloride, selegilinehydrochloride, tolcapone, and trihexyphenidyl hydrochloride. The atleast one miscellaneous central nervous system drug can be at least oneselected from bupropion hydrochloride, donepezil hydrochloride,droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate,naratriptan hydrochloride, nicotine polacrilex, nicotine transdermalsystem, propofol, rizatriptan benzoate, sibutramine hydrochloridemonohydrate, sumatriptan succinate, tacrine hydrochloride, andzolmitriptan. (See, e.g., pp. 337-530 of Nursing 2001 Drug Handbook.)

The at least one cholinergic (e.g., parasympathomimetic) can be at leastone selected from bethanechol chloride, edrophonium chloride,neostigmine bromide, neostigmine methylsulfate, physostigminesalicylate, and pyridostigmine bromide. The at least one anticholinergiccan be at least one selected from atropine sulfate, dicyclominehydrochloride, glycopyrrolate, hyoscyamine, hyoscyamine sulfate,propantheline bromide, scopolamine, scopolamine butylbromide, andscopolamine hydrobromide. The at least one adrenergic (sympathomimetics)can be at least one selected from dobutamine hydrochloride, dopaminehydrochloride, metaraminol bitartrate, norepinephrine bitartrate,phenylephrine hydrochloride, pseudoephedrine hydrochloride, andpseudoephedrine sulfate. The at least one adrenergic blocker(sympatholytic) can be at least one selected from dihydroergotaminemesylate, ergotamine tartrate, methysergide maleate, and propranololhydrochloride. The at least one skeletal muscle relaxant can be at leastone selected from baclofen, carisoprodol, chlorzoxazone, cyclobenzaprinehydrochloride, dantrolene sodium, methocarbamol, and tizanidinehydrochloride. The at least one neuromuscular blocker can be at leastone selected from atracurium besylate, cisatracurium besylate,doxacurium chloride, mivacurium chloride, pancuronium bromide,pipecuronium bromide, rapacuronium bromide, rocuronium bromide,succinylcholine chloride, tubocurarine chloride, and vecuronium bromide.(See, e.g., pp. 531-84 of Nursing 2001 Drug Handbook.)

The at least one antihistamine can be at least one selected frombrompheniramine maleate, cetirizine hydrochloride, chlorpheniraminemaleate, clemastine fumarate, cyproheptadine hydrochloride,diphenhydramine hydrochloride, fexofenadine hydrochloride, loratadine,promethazine hydrochloride, promethazine theoclate, and triprolidinehydrochloride. The at least one bronchodilator can be at least oneselected from albuterol, albuterol sulfate, aminophylline, atropinesulfate, ephedrine sulfate, epinephrine, epinephrine bitartrate,epinephrine hydrochloride, ipratropium bromide, isoproterenol,isoproterenol hydrochloride, isoproterenol sulfate, levalbuterolhydrochloride, metaproterenol sulfate, oxtriphylline, pirbuterolacetate, salmeterol xinafoate, terbutaline sulfate, and theophylline.The at least one expectorant or antitussive can be at least one selectedfrom benzonatate, codeine phosphate, codeine sulfate, dextramethorphanhydrobromide, diphenhydramine hydrochloride, guaifenesin, andhydromorphone hydrochloride. The at least one miscellaneous respiratorydrug can be at least one selected from acetylcysteine, beclomethasonedipropionate, beractant, budesonide, calfactant, cromolyn sodium, domasealfa, epoprostenol sodium, flunisolide, fluticasone propionate,montelukast sodium, nedocromil sodium, palivizumab, triamcinoloneacetonide, zafirlukast, and zileuton. (See, e.g., pp. 585-642 of Nursing2001 Drug Handbook.)

The at least one antacid, adsorbent, or antiflatulent can be at leastone selected from aluminum carbonate, aluminum hydroxide, calciumcarbonate, magaldrate, magnesium hydroxide, magnesium oxide,simethicone, and sodium bicarbonate. The at least one digestive enzymeor gallstone solubilizer can be at least one selected from pancreatin,pancrelipase, and ursodiol. The at least one antidiarrheal can be atleast one selected from attapulgite, bismuth subsalicylate, calciumpolycarbophil, diphenoxylate hydrochloride and atropine sulfate,loperamide, octreotide acetate, opium tincture, and opium tincure(camphorated). The at least one laxative can be at least one selectedfrom bisocodyl, calcium polycarbophil, cascara sagrada, cascara sagradaaromatic fluidextract, cascara sagrada fluidextract, castor oil,docusate calcium, docusate sodium, glycerin, lactulose, magnesiumcitrate, magnesium hydroxide, magnesium sulfate, methylcellulose,mineral oil, polyethylene glycol or electrolyte solution, psyllium,senna, and sodium phosphates. The at least one antiemetic can be atleast one selected from chlorpromazine hydrochloride, dimenhydrinate,dolasetron mesylate, dronabinol, granisetron hydrochloride, meclizinehydrochloride, metocloproamide hydrochloride, ondansetron hydrochloride,perphenazine, prochlorperazine, prochlorperazine edisylate,prochlorperazine maleate, promethazine hydrochloride, scopolamine,thiethylperazine maleate, and trimethobenzamide hydrochloride. The atleast one antiulcer drug can be at least one selected from cimetidine,cimetidine hydrochloride, famotidine, lansoprazole, misoprostol,nizatidine, omeprazole, rabeprozole sodium, rantidine bismuth citrate,ranitidine hydrochloride, and sucralfate. (See, e.g., pp. 643-95 ofNursing 2001 Drug Handbook.)

The at least one coricosteroid can be at least one selected frombetamethasone, betamethasone acetate or betamethasone sodium phosphate,betamethasone sodium phosphate, cortisone acetate, dexamethasone,dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisoneacetate, hydrocortisone, hydrocortisone acetate, hydrocortisonecypionate, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, prednisolone, prednisolone acetate,prednisolone sodium phosphate, prednisolone tebutate, prednisone,triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. Theat least one androgen or anabolic steroid can be at least one selectedfrom danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate,nandrolone phenpropionate, testosterone, testosterone cypionate,testosterone enanthate, testosterone propionate, and testosteronetransdermal system. The at least one estrogen or progestin can be atleast one selected from esterified estrogens, estradiol, estradiolcypionate, estradiol/norethindrone acetate transdermal system, estradiolvalerate, estrogens (conjugated), estropipate, ethinyl estradiol,ethinyl estradiol and desogestrel, ethinyl estradiol and ethynodioldiacetate, ethinyl estradiol and desogestrel, ethinyl estradiol andethynodiol diacetate, ethinyl estradiol and levonorgestrel, ethinylestradiol and norethindrone, ethinyl estradiol and norethindroneacetate, ethinyl estradiol and norgestimate, ethinyl estradiol andnorgestrel, ethinyl estradiol and norethindrone and acetate and ferrousfumarate, levonorgestrel, medroxyprogesterone acetate, mestranol andnorethindron, norethindrone, norethindrone acetate, norgestrel, andprogesterone. The at least one gonadroptropin can be at least oneselected from ganirelix acetate, gonadoreline acetate, histrelinacetate, and menotropins. The at least one antidiabetic or glucaon canbe at least one selected from acarbose, chlorpropamide, glimepiride,glipizide, glucagon, glyburide, insulins, metformin hydrochloride,miglitol, pioglitazone hydrochloride, repaglinide, rosiglitazonemaleate, and troglitazone. The at least one thyroid hormone can be atleast one selected from levothyroxine sodium, liothyronine sodium,liotrix, and thyroid. The at least one thyroid hormone antagonist can beat least one selected from methimazole, potassium iodide, potassiumiodide (saturated solution), propylthiouracil, radioactive iodine(sodium iodide .sup.131I), and strong iodine solution. The at least onepituitary hormone can be at least one selected from corticotropin,cosyntropin, desmophressin acetate, leuprolide acetate, repositorycorticotropin, somatrem, somatropin, and vasopressin. The at least oneparathyroid-like drug can be at least one selected from calcifediol,calcitonin (human), calcitonin (salmon), calcitriol, dihydrotachysterol,and etidronate disodium. (See, e.g., pp. 696-796 of Nursing 2001 DrugHandbook.)

The at least one diuretic can be at least one selected fromacetazolamide, acetazolamide sodium, amiloride hydrochloride,bumetanide, chlorthalidone, ethacrynate sodium, ethacrynic acid,furosemide, hydrochlorothiazide, indapamide, mannitol, metolazone,spironolactone, torsemide, triamterene, and urea. The at least oneelectrolyte or replacement solution can be at least one selected fromcalcium acetate, calcium carbonate, calcium chloride, calcium citrate,calcium glubionate, calcium gluceptate, calcium gluconate, calciumlactate, calcium phosphate (dibasic), calcium phosphate (tribasic),dextran (high-molecular-weight), dextran (low-molecular-weight),hetastarch, magnesium chloride, magnesium sulfate, potassium acetate,potassium bicarbonate, potassium chloride, potassium gluconate, Ringer'sinjection, Ringer's injection (lactated), and sodium chloride. The atleast one acidifier or alkalinizer can be at least one selected fromsodium bicarbonate, sodium lactate, and tromethamine. (See, e.g., pp.797-833 of Nursing 2001 Drug Handbook.)

The at least one hematinic can be at least one selected from ferrousfumarate, ferrous gluconate, ferrous sulfate, ferrous sulfate (dried),iron dextran, iron sorbitol, polysaccharide-iron complex, and sodiumferric gluconate complex. The at least one anticoagulant can be at leastone selected from ardeparin sodium, dalteparin sodium, danaparoidsodium, enoxaparin sodium, heparin calcium, heparin sodium, and warfarinsodium. The at least one blood derivative can be at least one selectedfrom albumin 5%, albumin 25%, antihemophilic factor, anti-inhibitorcoagulant complex, antithrombin III (human), factor IX (human), factorIX complex, and plasma protein fractions. The at least one thrombolyticenzyme can be at least one selected from alteplase, anistreplase,reteplase (recombinant), streptokinase, and urokinase. (See, e.g., pp.834-66 of Nursing 2001 Drug Handbook.)

The at least one alkylating drug can be at least one selected frombusulfan, carboplatin, carmustine, chlorambucil, cisplatin,cyclophosphamide, ifosfamide, lomustine, mechlorethamine hydrochloride,melphalan, melphalan hydrochloride, streptozocin, temozolomide, andthiotepa. The at least one antimetabolite can be at least one selectedfrom capecitabine, cladribine, cytarabine, floxuridine, fludarabinephosphate, fluorouracil, hydroxyurea, mercaptopurine, methotrexate,methotrexate sodium, and thioguanine. The at least one antibioticantineoplastic can be at least one selected from bleomycin sulfate,dactinomycin, daunorubicin citrate liposomal, daunorubicinhydrochloride, doxorubicin hydrochloride, doxorubicin hydrochlorideliposomal, epirubicin hydrochloride, idarubicin hydrochloride,mitomycin, pentostatin, plicamycin, and valrubicin. The at least oneantineoplastic that alters hormone balance can be at least one selectedfrom anastrozole, bicalutamide, estramustine phosphate sodium,exemestane, flutamide, goserelin acetate, letrozole, leuprolide acetate,megestrol acetate, nilutamide, tamoxifen citrate, testolactone, andtoremifene citrate. The at least one miscellaneous antineoplastic can beat least one selected from asparaginase, bacillus Calmette-Guerin (BCG)(live intravesical), dacarbazine, docetaxel, etoposide, etoposidephosphate, gemcitabine hydrochloride, irinotecan hydrochloride,mitotane, mitoxantrone hydrochloride, paclitaxel, pegaspargase, porfimersodium, procarbazine hydrochloride, rituximab, teniposide, topotecanhydrochloride, trastuzumab, tretinoin, vinblastine sulfate, vincristinesulfate, and vinorelbine tartrate. (See, e.g., pp. 867-963 of Nursing2001 Drug Handbook.)

The at least one immunosuppressant can be at least one selected fromazathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immuneglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetilhydrochloride, sirolimus, and tacrolimus. The at least one vaccine ortoxoid can be at least one selected from BCG vaccine, cholera vaccine,diphtheria and tetanus toxoids (adsorbed), diphtheria and tetanustoxoids and acellular pertussis vaccine adsorbed, diphtheria and tetanustoxoids and whole-cell pertussis vaccine, Haemophilus b conjugatevaccines, hepatitis A vaccine (inactivated), hepatitis B vaccine(recombinant), influenza virus vaccine 1999-2000 trivalent types A & B(purified surface antigen), influenza virus vaccine 1999-2000 trivalenttypes A & B (subvirion or purified subvirion), influenza virus vaccine1999-2000 trivalent types A & B (whole virion), Japanese encephalitisvirus vaccine (inactivated), Lyme disease vaccine (recombinant OspA),measles and mumps and rubella virus vaccine (live), measles and mumpsand rubella virus vaccine (live attenuated), measles virus vaccine (liveattenuated), meningococcal polysaccharide vaccine, mumps virus vaccine(live), plague vaccine, pneumococcal vaccine (polyvalent), poliovirusvaccine (inactivated), poliovirus vaccine (live, oral, trivalent),rabies vaccine (adsorbed), rabies vaccine (human diploid cell), rubellaand mumps virus vaccine (live), rubella virus vaccine (live,attenuated), tetanus toxoid (adsorbed), tetanus toxoid (fluid), typhoidvaccine (oral), typhoid vaccine (parenteral), typhoid Vi polysaccharidevaccine, varicella virus vaccine, and yellow fever vaccine. The at leastone antitoxin or antivenin can be at least one selected from black widowspider antivenin, Crotalidae antivenom (polyvalent), diphtheriaantitoxin (equine), and Micrurus fulvius antivenin. The at least oneimmune serum can be at least one selected from cytomegalovirus immuneglobulin (intraveneous), hepatitis B immune globulin (human), immuneglobulin intramuscular, immune globulin intravenous, rabies immuneglobulin (human), respiratory syncytial virus immune globulinintravenous (human), Rh.sub.0(D) immune globulin (human), Rh.sub.0(D)immune globulin intravenous (human), tetanus immune globulin (human),and varicella-zoster immune globulin. The at least one biologicalresponse modifier can be at least one selected from aldesleukin, epoetinalfa, filgrastim, glatiramer acetate for injection, interferonalfacon-1, interferon alfa-2a (recombinant), interferon alfa-2b(recombinant), interferon beta-1a, interferon beta-1b (recombinant),interferon gamma-1b, levamisole hydrochloride, oprelvekin, andsargramostim. (See, e.g., pp. 964-1040 of Nursing 2001 Drug Handbook.)

The at least one ophthalmic anti-infective can be selected formbacitracin, chloramphenicol, ciprofloxacin hydrochloride, erythromycin,gentamicin sulfate, ofloxacin 0.3%, polymyxin B sulfate, sulfacetamidesodium 10%, sulfacetamide sodium 15%, sulfacetamide sodium 30%,tobramycin, and vidarabine. The at least one ophthalmicanti-inflammatory can be at least one selected from dexamethasone,dexamethasone sodium phosphate, diclofenac sodium 0.1%, fluorometholone,flurbiprofen sodium, ketorolac tromethamine, prednisolone acetate(suspension) and prednisolone sodium phosphate (solution). The at leastone miotic can be at least one selected from acetylocholine chloride,carbachol (intraocular), carbachol (topical), echothiophate iodide,pilocarpine, pilocarpine hydrochloride, and pilocarpine nitrate. The atleast one mydriatic can be at least one selected from atropine sulfate,cyclopentolate hydrochloride, epinephrine hydrochloride, epinephrylborate, homatropine hydrobromide, phenylephrine hydrochloride,scopolamine hydrobromide, and tropicamide. The at least one ophthalmicvasoconstrictor can be at least one selected from naphazolinehydrochloride, oxymetazoline hydrochloride, and tetrahydrozolinehydrochloride. The at least one miscellaneous ophthalmic can be at leastone selected from apraclonidine hydrochloride, betaxolol hydrochloride,brimonidine tartrate, carteolol hydrochloride, dipivefrin hydrochloride,dorzolamide hydrochloride, emedastine difumarate, fluorescein sodium,ketotifen fumarate, latanoprost, levobunolol hydrochloride, metipranololhydrochloride, sodium chloride (hypertonic), and timolol maleate. The atleast one otic can be at least one selected from boric acid, carbamideperoxide, chloramphenicol, and triethanolamine polypeptideoleate-condensate. The at least one nasal drug can be at least oneselected from beclomethasone dipropionate, budesonide, ephedrinesulfate, epinephrine hydrochloride, flunisolide, fluticasone propionate,naphazoline hydrochloride, oxymetazoline hydrochloride, phenylephrinehydrochloride, tetrahydrozoline hydrochloride, triamcinolone acetonide,and xylometazoline hydrochloride. (See, e.g., pp. 1041-97 of Nursing2001 Drug Handbook.)

The at least one local anti-infective can be at least one selected fromacyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazolenitrate, clindamycin phosphate, clotrimazole, econazole nitrate,erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate,metronidazole (topical), miconazole nitrate, mupirocin, naftifinehydrochloride, neomycin sulfate, nitrofurazone, nystatin, silversulfadiazine, terbinafine hydrochloride, terconazole, tetracyclinehydrochloride, tioconazole, and tolnaftate. The at least one scabicideor pediculicide can be at least one selected from crotamiton, lindane,permethrin, and pyrethrins. The at least one topical corticosteroid canbe at least one selected from betamethasone dipropionate, betamethasonevalerate, clobetasol propionate, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate,fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasonepropionate, halcionide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocorisone valerate, mometasone furoate, andtriamcinolone acetonide. (See, e.g., pp. 1098-1136 of Nursing 2001 DrugHandbook.)

The at least one vitamin or mineral can be at least one selected fromvitamin A, vitamin B complex, cyanocobalamin, folic acid,hydroxocobalamin, leucovorin calcium, niacin, niacinamide, pyridoxinehydrochloride, riboflavin, thiamine hydrochloride, vitamin C, vitamin D,cholecalciferol, ergocalciferol, vitamin D analogue, doxercalciferol,paricalcitol, vitamin E, vitamin K analogue, phytonadione, sodiumfluoride, sodium fluoride (topical), trace elements, chromium, copper,iodine, manganese, selenium, and zinc. The at least one caloric can beat least one selected from amino acid infusions (crystalline), aminoacid infusions in dextrose, amino acid infusions with electrolytes,amino acid infusions with electrolytes in dextrose, amino acid infusionsfor hepatic failure, amino acid infusions for high metabolic stress,amino acid infusions for renal failure, dextrose, fat emulsions, andmedium-chain triglycerides. (See, e.g., pp. 1137-63 of Nursing 2001 DrugHandbook.)

The compositions provided by the present invention can further compriseat least one of any suitable and effective amount of a composition orpharmaceutical composition comprising at least one of an anti-IL-12antibody contacted or administered to a cell, tissue, organ, animal orpatient in need of such modulation, treatment or therapy, a TNFantagonist (e.g., but not limited to a TNF chemical or proteinantagonist, TNF monoclonal or polyclonal antibody or fragment, a solubleTNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptidesthereof, or a small molecule TNF antagonist, e.g., TNF binding protein Ior II (TBP-1 or TBP-II), nerelimonmab, infliximab, etemacept, CDP-571,CDP-870, afelimomab, lenercept, and the like), an antirheumatic (e.g.,methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, goldsodium thiomalate, hydroxychloroquine sulfate, leflunomide,sulfasalzine), a muscle relaxant, a narcotic, a non-steroidanti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative,a local anethetic, a neuromuscular blocker, an antimicrobial (e.g.,aminoglycoside, an antifungal, an antiparasitic, an antiviral, acarbapenem, cephalosporin, a fluororquinolone, a macrolide, apenicillin, a sulfonamide, a tetracycline, another antimicrobial), anantipsoriatic, a corticosteriod, an anabolic steroid, a diabetes relatedagent, a mineral, a nutritional, a thyroid agent, a vitamin, a calciumrelated hormone, an antidiarrheal, an antitussive, an antiemetic, anantiulcer, a laxative, an anticoagulant, an erythropoietin (e.g.,epoetin alpha), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim(GM-CSF, Leukine), an immunization, an immunoglobulin, animmunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), agrowth hormone, a hormone replacement drug, an estrogen receptormodulator, a mydriatic, a cycloplegic, an alkylating agent, anantimetabolite, a mitotic inhibitor, a radiopharmaceutical, anantidepressant, antimanic agent, an antipsychotic, an anxiolytic, ahypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthmamedication, a beta agonist, an inhaled steroid, a leukotriene inhibitor,a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha(Pulmozyme), a cytokine or a cytokine antagonist. Non-limiting examplesof such cytokines include, but are not limited to, any of IL-1 to IL-23(e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art.See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2.sup.ndEdition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing,Loma Linda, Calif. (2000), each of which references are entirelyincorporated herein by reference.

Such anti-cancer or anti-infectives can also include toxin moleculesthat are associated, bound, co-formulated or co-administered with atleast one antibody of the present invention. The toxin can optionallyact to selectively kill the pathologic cell or tissue. The pathologiccell can be a cancer or other cell. Such toxins can be, but are notlimited to, purified or recombinant toxin or toxin fragment comprisingat least one functional cytotoxic domain of toxin, e.g., selected fromat least one of ricin, diphtheria toxin, a venom toxin, or a bacterialtoxin. The term toxin also includes both endotoxins and exotoxinsproduced by any naturally occurring, mutant or recombinant bacteria orviruses which may cause any pathological condition in humans and othermammals, including toxin shock, which can result in death. Such toxinsmay include, but are not limited to, enterotoxigenic E. coli heat-labileenterotoxin (LT), heat-stable enterotoxin (ST), Shigella cytotoxin,Aeromonas enterotoxins, toxic shock syndrome toxin-1 (TSST-1),Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcalenterotoxins and the like. Such bacteria include, but are not limitedto, strains of a species of enterotoxigenic E. coli (ETEC),enterohemorrhagic E. coli (e.g., strains of serotype 0157:H7),Staphylococcus species (e.g., Staphylococcus aureus, Staphylococcuspyogenes), Shigella species (e.g., Shigella dysenteriae, Shigellaflexneri, Shigella boydii, and Shigella sonnei), Salmonella species(e.g., Salmonella typhi, Salmonella cholera-suis, Salmonellaenteritidis), Clostridium species (e.g., Clostridium perfringens,Clostridium dificile, Clostridium botulinum), Camphlobacter species(e.g., Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species,(e.g., Heliobacter pylori), Aeromonas species (e.g., Aeromonas sobria,Aeromonas hydrophila, Aeromonas caviae), Pleisomonas shigelloides,Yersina enterocolitica, Vibrios species (e.g., Vibrios cholerae, Vibriosparahemolyticus), Klebsiella species, Pseudomonas aeruginosa, andStreptococci. See, e.g., Stein, ed., INTERNAL MEDICINE, 3rd ed., pp1-13, Little, Brown and Co., Boston, (1990); Evans et al., eds.,Bacterial Infections of Humans: Epidemiology and Control, 2d. Ed., pp239-254, Plenum Medical Book Co., New York (1991); Mandell et al,Principles and Practice of Infectious Diseases, 3d. Ed., ChurchillLivingstone, New York (1990); Berkow et al, eds., The Merck Manual, 16thedition, Merck and Co., Rahway, N.J., 1992; Wood et al, FEMSMicrobiology Immunology, 76:121-134 (1991); Marrack et al, Science,248:705-711 (1990), the contents of which references are incorporatedentirely herein by reference.

In any embodiment described herein, the compositions provided by theinvention can be administered by any pharmaceutically acceptable route,for example, oral, anal, vaginal, nasal, enteral, parenteral,intravenous, intraperitoneal, sublingual, percutaneous, topical, viainhalation, and the like. Systemic formulations include those designedfor administration by injection, e.g. subcutaneous, intravenous,intramuscular, intrathecal or intraperitoneal injection, as well asthose designed for transdermal, transmucosal, oral or pulmonaryadministration. Similarly, the composition of the invention can be inany suitable form, for example, liquid, gel, cream, aerosol, lotion, andthe like.

For injection, the solution may contain additional formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the proteins may be in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

For administration by inhalation, the composition for use according tothe present invention are conveniently delivered in the form of anaerosol spray from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount. Forexample, liposomes and emulsions are well known examples of deliveryvehicles that may be used in conjunction with the composition of theinvention to deliver a biologically active agent.

As used herein, an “effective amount” or “therapeutically effectivedose” refers to that amount of the therapeutic sufficient to prevent,delay, inhibit the occurrence, or treat (alleviate a symptom to someextent, preferably all of the symptoms) of a disease state. Theeffective amount or dose depends on the type of disease, the compositionused, the route of administration, the type of mammal being treated, thephysical characteristics of the specific mammal under consideration,concurrent medication, and other factors which those skilled in themedical arts will recognize.

A suitable dose is an amount/rate/volume of the composition that, whenadministered as described above, is capable of ameliorating or reducingtissue and/or cellular damage observed with saline or Ringer's solution.Suitable dose rates of administration will also vary with a number offactors, for example, patient size, procedure type, duration, and thelike. Dose rates will typically range from about 1 mL/min to about 500mL/min. In general, the amount of composition administered in a dosewill range from about 0.1 mL to about 500 mL per kg of host, typicallyfrom 1 mL to about 50 liters.

Determination of an effective amount of the composition of the inventionfor use in, for example, in vitro culture of cells or tissues,veterinary surgical procedures or human surgical procedures is wellwithin the capabilities of those skilled in the art, especially in lightof the detailed disclosure provided herein. An effective dose can beestimated initially from in vitro assays. For example, a dose and/orperfusion rate and volume can be formulated in animal models to achievethe desired amelioration of tissue and cellular damage using techniquesthat are well known in the art. One having ordinary skill in the artcould readily optimize administration to humans based on animal data.Dosage amount and interval may be adjusted individually. For example,the invention may be administered in a single dose, multiple dosageadministered at discrete time points, or administered continuouslyduring a portion of or throughout the entire procedure. Alternateprotocols may be appropriate for individual patients. A suitable dose isan amount/rate/volume of the composition that, when administered asdescribed above, is capable of ameliorating or reducing tissue and/orcellular damage observed with saline or Ringer's solution.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD50/ED50.Compounds that exhibit large therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects. The data obtainedfrom the cell culture assays and animal studies can be used informulating a range of dosage for use in humans. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED50 with little or no toxicity.

Generally, for an active ingredient an amount between 0.1 mg/kg and 1000mg/kg body weight/day of active ingredients is administered dependentupon potency of the active ingredient(s). The dosage may vary withinthis range depending upon the particular API, dosage form employed, andthe route of administration utilized. For any compound used in themethod of the invention, the therapeutically effective dose can beestimated initially from cell culture, and/or animal assays. A dose maybe formulated in animal models to achieve a circulating plasmaconcentration range that includes the IC50 (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

Determination of an effective amount of the composition of the inventionfor use in, for example, in vitro culture of cells or tissues,veterinary surgical procedures or human surgical procedures is wellwithin the capabilities of those skilled in the art, especially in lightof the detailed disclosure provided herein. An effective dose can beestimated initially from in vitro assays. For example, a dose and/orperfusion rate and volume can be formulated in animal models to achievethe desired amelioration of tissue and cellular damage using techniquesthat are well known in the art. One having ordinary skill in the artcould readily optimize administration to humans based on animal data.Dosage amount and interval may be adjusted individually. For example,the invention may be administered in a single dose, multiple dosageadministered at discrete time points, or administered continuouslyduring a portion of or throughout the entire procedure. Alternateprotocols may be appropriate for individual patients.

The contents of all references, patents, pending patent applications andpublished patents, cited throughout this application are herebyexpressly incorporated by reference. Those skilled in the art willrecognize, or be able to ascertain using no more than routineexperimentation, many equivalents to the specific embodiments of theinvention described herein. Such equivalents are intended to beencompassed by the following claims.

It is understood that the detailed examples and embodiments describedherein are given by way of example for illustrative purposes only, andare in no way considered to be limiting to the invention. Variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are included within the spirit and purview ofthis application and are considered within the scope of the appendedclaims. For example, the relative quantities of the ingredients may bevaried to optimize the desired effects, additional ingredients may beadded, and/or similar ingredients may be substituted for one or more ofthe ingredients described. Additional advantageous features andfunctionalities associated with the systems, methods, and processes ofthe present invention will be apparent from the appended claims.Moreover, those skilled in the art will recognize, or be able toascertain using no more than routine experimentation, many equivalentsto the specific embodiments of the invention described herein. Suchequivalents are intended to be encompassed by the following claims.

EXAMPLES

The following non-limiting examples are described further, below, withreference to FIGS. 1-7. In particular, although the examples wereperformed using articular cartilage chondrocytes, the invention is notlimited thereto. For example, as would be appreciated by the skilledartisan, the compositions provided by the invention would be suitablefor use in procedures involving any cell or tissue type.

Example 1

FIG. 1 demonstrates the results obtained in assays using one embodimentof the present invention. In this exemplary embodiment, the compositioncomprises isotonic phosphate buffered saline, high molecular weightdextran, ascorbate, transferrin, and the poloxamer surfactant P188. Inthis experiment, full thickness discs (about 6 mm diameter) of articularcartilage from the bovine radial-carpal joint are immersed in varioussolutions for about 24 hours or about 48 hours, respectively. After theimmersion step, the cartilage is cut into 70 μm sections on a vibratomeand stained with Syto 13 (Molecular Probes) and ethidium bromide toassess chondrocyte viability.

FIG. 1 demonstrates the local anesthetic bupivacaine ((bup+PBS, 1.25mg/mL [0.125%]) causes chondrocyte death at about 24 hours(approximately 35% chondrocytes death) and at about 48 hours(approximately 68.5% chondrocyte death) when articular cartilage isbathed in a solution of 1.25 mg/mL bupivacaine ([0.125%] phosphatebuffered saline with bupivicaine). When the solution as provided by theinvention is used with the same concentration of bupivacaine(bup+arthroguard), chondrocyte death is reduced to approximately 17% atabout 24 hours and approximately 20% at about 48 hours.

The results indicate that the exemplary embodiment of the composition ofthe invention was surprisingly and unexpectedly successful at reducingor ameliorating cell death (necrosis and/or apoptosis) that occurs inthe presence of anesthetic.

Example 2

FIG. 1 also demonstrates the observed results attained using anotherexemplary embodiment of the present invention. In particular, theadjuvant composition additionally comprises epinephrine, andbupivacaine. When epinephrine (5 ug/mL) is added to the solution ofphosphate buffered saline with bupivacaine (1.25 mg/mL [0.125%]),chondrocyte death is approximately 53.5% at about 24 hours andapproximately 97.5% at about 48 hours (bup/epi/PBS). On the other hand,when the cells are exposed to the arthroguard solution containing thesame concentrations of epinephrine and bupivacaine (bup/epi/AG),chondrocyte death is reduced to approximately 29% at about 24 hours andapproximately 48% at about 48 hours.

Example 3

FIG. 2 shows that substantial chondrocyte death occurs in thesuperficial zone of articular cartilage when bathed in saline for about24 and about 48 hours, respectively. The superficial zone is taken asthe region from the articular surface to 1/10 the distance to thecalcified zone. Chondrocyte death in the superficial zone is reduced inRinger's Lactate at 24 hours but not at 48 hours. As above, fullthickness discs (about 6 mm diameter) of articular cartilage from thebovine radial-carpal joint are immersed in various solutions for about24 or about 48 hours, respectively, after which the cartilage is cutinto 70 μm sections on a vibratome and stained with Syto 13 (MolecularProbes) and ethidium bromide to assess chondrocyte viability.

The results demonstrate the surprising and unexpected finding thatchondrocyte death is substantially reduced at both 24 and 48 hours whenthe cartilage is bathed in the arthroguard adjuvant when compared toboth saline and Ringer's Lactate solutions.

Example 4

FIG. 6 shows that substantial cell death occurs in a buffered, isotonicmedium when incubated at 45° C. beginning at 30 minutes. This form ofcell death is prevented when the cells are incubated in the arthroguardsolution at the same temperature, for at least two hours.

This result demonstrates the surprising and unexpected finding that celldeath due to exposure to high temperatures is substantially reduced whenthe cells are bathed in the arthroguard adjuvant when compared tophosphate buffered saline.

Example 5

FIG. 7 shows that chondrocytes that have been isolated from thecartilage matrix lose viability when suspended in conventional irrigantsolutions such as saline and phosphate buffered saline (PBS). Theaddition of the anaesthetic bupivicaine increases the amount of celldeath. The addition of arthroguard allows the cells to maintainviability for the duration of the experiment (12 hrs) and substantiallyreduces the amount of cell death when the cells are exposed tobupivicaine.

This result demonstrates the surprising and unexpected finding thatchondrocytes that have been isolated from the cartilage matrix are alsoprotected by the arthroguard adjuvant from cell death caused bybupivicaine and by prolonged incubation in isotonic saline solutions.

FIG. 3 demonstrates the observed results attained using anotherexemplary embodiment of the present invention. In particular, theadjuvant composition additionally comprises epinephrine, andbupivicaine. When epinephrine is added to the solution of phosphatebuffered saline with bupivicaine, chondrocyte death is approximately53.5% at about 24 hours and approximately 97.5% at about 48 hours. Onthe other hand, when the cells are exposed to the arthroguard solutioncontaining the same concentrations of epinephrine and bupivicaine,chondrocyte death is reduced to approximately 29% at about 24 hours andapproximately 48% at about 48 hours.

Having described preferred embodiments of the invention with referenceto the accompanying drawings, it is to be understood that the inventionis not limited to the precise embodiments, and that various changes andmodifications may be effected therein by those skilled in the artwithout departing from the scope or spirit of the invention as definedin the appended claims. Accordingly, the detailed description is to betaken in an illustrative, as opposed to a limiting sense.

What is claimed is:
 1. A method for ameliorating tissue or cellulardamage in a patient due to an invasive procedure comprisingadministering to the patient an effective amount of an adjuvantcomprising isotonic phosphate buffered saline a high molecular weightdextran, ascorbate, transferrin, and poloxamer surfactant P188 before,during, and/or after a surgical procedure, wherein the compositionameliorates tissue or cellular damage.
 2. The method of claim 1, whereinthe adjuvant further comprises an anesthetic.
 3. The method of claim 1,wherein the adjuvant further comprises epinephrine.
 4. The method ofclaim 1, wherein the procedure is an arthroscopic surgical procedure. 5.The method of claim 1, wherein the procedure is a minimally invasiveendoscopic surgical procedure.
 6. The method of claim 1, wherein thecomposition is administered prior to the procedure.
 7. The method ofclaim 1, wherein the composition is administered during the procedure.8. The method of claim 1, wherein the composition is administered afterthe procedure.
 9. The method of claim 1, wherein the composition isadministered at multiple times selected from the group consisting ofbefore the procedure, during the procedure, after the procedure, andcombinations thereof.
 10. The method of claim 1, wherein the compositionis administered continuously during a portion of or throughout theentire procedure.
 11. The method of claim 10, wherein the continuouslyfor at least one time interval selected from the group consisting of: atime point prior to the procedure until the procedure is complete, atime point during the procedure until a time point after the procedureor, a time point prior to the procedure until a time point after theprocedure.